Targeted Therapies inEpilepsy

Mary B. Connolly

BC Children’s Hospital and UBC

Trials supported by

Biocodex

Novartis

Sage Therapeutics

I will discuss available data on targeted treatments in specific conditions which are off label or not standard therapy.

Disclosures

Objectives

To discuss precision medicine in epilepsy in 2017

To review targeted therapy in neurometabolic disorders, channelopathies, TSC and several specific gene disorders

To review current state of pharmacogenomics in epilepsy

Speculate about how treatment of epileptology will evolve over next few years

3

Epilepsy Challenges in 2017 Seizures remain treatment resistant in 30-40% of

individuals despite new AEDs and other advances.

Surgery is underutilized.

Cognitive and neuropsychiatric co-morbidity high.

Mortality remains high.

Epilepsy genetics shifting from academic pursuit of gene discovery to a clinical discipline based on molecular diagnosis and stratified medicine.

However, in 2017 only a small percentage of patients benefit from precision or targeted therapies

Goals of Epilepsy Treatment

Cure of disease

Control of seizures with absence of side effects

Balance of therapeutic effect and side effects, costs and benefits

Treatment of Epilepsy in 2017

Anti-seizure medications

Dietary therapies

Surgery

Brain Modulation Vagus nerve stimulation, Deep brain stimulation,

Responsive stimulation

Thermocoagulation

Precision treatment guided by genomics

Repurposing of other drugs

Epilepsy in Children: Impact on Learning

Prospective cohort of children with epilepsy diagnosed < 8 years

Early age at seizure onset and pharmaco-resistance resulted in lower IQ

Pharmaco-resistance had most profound impact in 0-3 year group

Berg et al., Neurology 2012

Precision Medicine: Francis Collins

Medicine for most of human history has been one-size-fits-all. But we’re all different, and we’re finding out that the diseases we have lumped together under one label are actually at the molecular level quite distinct.

Precision medicine tries to understand what’s underneath those disease layers and tries not to lump everyone together but think about individual differences.

Essence of Precision Treatment

Is it possible to predict which patients will respond best to a specific treatment

Is there a specific or novel therapy for individual based on genes or pathway involved in causing their epilepsy

Can we predict which patients will develop side effects of treatment

EpiPM Consortium Lancet Neurol 2015; Symonds et al. Current OpinNeurol 2017;

Treatable Neurometabolic Diseases

Rare diseases

Important not to miss diagnosis

Number of treatable metabolic diseases increasing (now ~84)

Newborn screening detects some disorders

Major research interest of team at BCCH (Treatable Intellectual Disability Endeavour -TIDE)

App available to guide physicians with investigations

Inherited Metabolic Epilepsies

Vitamin responsive (B6, PNP, Biotinidase)

Transporter (GLUT1, Cerebral Folate)

Aminoacid and organic disorders (Serine synthesis, Creatine synthesis)

Mitochondrial disorders (KD)

Urea Cycle disorders

Neurotransmitter disorders

Disorders of glucose homeostasis

Pyridoxine Dependent Epilepsy

• Historically diagnosis trial of pyridoxine

• Biomarkers: urine AASA

• Testing for Antiquitin gene mutations

• Can be diagnosed with NGS

• Treatment with pyridoxine alone not effective in all patients

GLUCOSE TRANSPORTER 1 Deficiency: Variable Clinical Features (SLC2A1)

Neonate

• Main manifestations:– Seizures– Apnea– Abnormal eye

movements

Older children

• Paroxysmal:– Alternating hemiplegia – Intermittent ataxia– Headache, confusion

• Permanent:– Mental retardation– Ataxia– Spasticity

GLUCOSE TRANSPORTER 1 Deficiency

Creatine Def Syndromes (CDS) GAMT, AGAT, CRTR

Sodium Channel Disorders (SCN) In CNS: 4 major SCN family

SCN1A (Nav1.1, 2q24): Dravet syndrome (DS), FS+, FHM3, SUDEP

SCN2A (Nav1.2, 2q24): BFNIS, GEFS+, MFEI, OS, EOEE, DS

SCN3A (Nav1.3, 2q24): Unclear SCN8A (Nav1.6, 12q13): EE

Brunkaus A et al., J Med Genet 2014

Dravet Syndrome

• 1978: 1st described by Charlotte Dravet• Seizure onset: 1st year of life • Hemiclonic or generalized TC seizures • Other seizure types• Normal development prior to seizure onset• Moderate to severe intellectual impairment

Ataxia and crouched gait • Mortality ~ 10%

EpGEN StudyPhenotype Gene Impact on Management

Dravet Syndrome SCN1A Antiepileptic medication change

Alpers Syndrome POLG Stopped valproic acid, early palliative care

Self limited familial neonatal epilepsy

KCNQ2 Stopped antiepileptic medication

Adenylsuccinate Lyase Deficiency ADSL Earlier consideration to use ketogenic diet; S-Adenosyl-I-methionine trial

Hemiplegic MigraineEpilepsy

ATP1A2 Stopped stiripentol; started flunarazine

KCNQ2 Encephalopathy KCNQ2 Antiepileptic medication change

KCNQ2 Encephalopathy KCNQ2 Antiepileptic medication change

CDG IIm SLC35A2 Galactose trial

Treatment of Dravet Syndrome

• Seizures treatment resistant in most patients

• Best options: Clobazam, Valproic acid, Topiramate, Stiripentol, Levetiracetam Ketogenic diet

• Avoid: Carbamazepine, Oxcarbazepine, Phenytoin, Lamotrigine, Vigabatrin, Phenobarbital, Rufinamide

Stiripentol

• Modulator of GABA

• Potentiates GABAergic inhibitory post-synaptic currents,maintaining phasic inhibition (by action on α4 GABAA

receptors and tonic inhibition

StiripentolStudy Design N Findings

Dressler et al. 2015

Open label, retrospective

9 All treated with VPA + CLB + STPResponder rate 89%, mean sz reduction 73%

Inoue et al. 2014

Open-label, prospective

24 67% responders (17% sz-free)Significant reduction in sz duration and use of rescue meds

Wirrell et al. 2013

Open-label, retrospective

82 Overall sz frequency reduced in 57-80% depending on co-therapyAll had reduction in frequency of prolonged szs and most had significant reduction in rescue med use and ER visits/hospitalizations

Inoue et al. 2009

Open label, prospective

23 >50% reduction in GTCS in 61% (9% sz free)

Thanh et al. 2002

Open-label, retrospective

46 Seizure frequency decreased by 66% (p<0.001)Reduction in sz duration (p<0.002), status epilepticus (p<0.001)

Fenfluramine

Amphetamine-like agent used as anti-obesity drug

Taken off market due to possible cardiac adverse effects (valve thickening, pulmonary hypertension)

Releases serotonin by disrupting vesicular storage and reversing 5HT transporter function

Fenfluramine

12 pts treated (mean dose 0.34, range 0.12-0.90 mg/kg/d) for mean of 11.4 yrs (range 1-19 yrs)

No pt had received STP, ketogenic diet or bromide

10 (83%) continued on fenfluramine at follow-up

7 (58%) were seizure free for longer than 1 year

Side effects:

Mild, non-progressive heart valve thickening in 2

Decreased appetite in 2

Ceulemans et al. Epilepsia 2012

Fenfluramine Studies in DS

Prospective studies

Children on VPA and Clobazam

75% reduction in major seizures

Children on Stiripentol, Clobazam, VPA

Study in Lennox-Gastaut syndrome about

Probable study in adults with DS

KCNQ2 Related Epilepsy

Phenotypes: Benign familial neonatal epilepsy

Epileptic encephalopathy

Encodes potassium voltage-gated channel subfamily KQT member 2

Drugs which act on sodium channels such as carbamazepine and phenytoin often effective

Retigabine shown to be effective in some patients

Adverse Effects of Retigabine

Blue skin discoloration and retinal pigment abnormalities

Urinary retention

KCNT1 Mutations

KCNT1: encodes a weak voltage-dependent and intracellular sodium-activated potassium channel.

Missense mutations:

Autosomal dominant nocturnal frontal lobe epilepsy

De novo gain of function:

Migrating focal epilepsy of infancy

Quinidine in KCNT1 Mutations

Made from Cinchona plant Broad spectrum K channel blocker (KCNT1) Anti arrythmic Patients with malignant migrating epilepsy have

responded to 34-60mg/kg/day Case reports of patients having improvement in

seizures and development with gain of function mutations

Targeted Therapy in Tuberous Sclerosis Complex

cortical tubers cytomegalic neuronsand balloon cells

mTOR pathway

Tuberous Sclerosis Complex (TSC)

90% develop epilepsy

Onset often in 1st year of life

Uncontrolled epilepsy: high risk of autism and intellectual impairment

Advances: Biomarkers of epilepsy and treatment prior to seizure onset

mTOR inhibitors effective for epilepsy

Problems in TSC

How do we predict which patients will do well with surgery?

When to use KD which has mTORinhibition?

What is role of mTOR drugs in epilepsy and how to access them?

mTOR Inhibitors and Epilepsy

TSC mouse models: Rapamycin reversed astrogliosis/neuronal disorganization

Prevent development of seizures Improve learning and attention

Clinical trials: Rapamycin reduced seizure frequency Everolimus Phase 1/2 and EXIST-1 SEGA trials showed

reduction of seizures in some patients EXIST 3 trial: Everolimus effective in reducing seizures

Tubers

Tubers are dynamic entities that evolve over time? Cyst-like cortical tubers progress on MRI Display reactive gliosis on pathology consistent

with a chronic process Elevated mTOR activity in tubers

Exist 3 Trial inTSC366 patients: placebo (n=119), low dose (n=117) or high dose (n=130)

Lee et al, Nature genetics. 2012; D'Gama et al, Annals of Neurology, 2015; French et al, Lancet 2016

>50% sz frequency reduction

15.1% placebo28.2% low dose40% high dose

Median percentage reduction in sz frequency:

14.9% with placebo 29.3% low exposure39.6% high exposure

mTOR Pathway and Other Disorders

Tuberous sclerosis Complex FCD Focal epilepsy without normal imaging Post-traumatic epilepsy Polyhydramnios megalencephaly symptomatic epilepsy

syndrome Neurofibromatoses 1 and 2, Peutz–Jeghers syndrome Cowden syndrome, Bannayan–Riley–Ruvalcaba syndrome Proteus syndrome Lhermitte–Duclos syndrome, von Hippel–Lindau

syndrome Huntington’s, Parkinson’s, Schizophrenia, Alzheimer’s Learning and memory

Role of mTOR Inhibitors

Reports of seizure control:– Focal Cortical Dysplasia (esp FCD II)– Polyhydramnios, Megencephaly and Symptomatic

Epilepsy– Hypothalamic Hamartoma

Pathways

Focal Cortical Dysplasia: Genetic Aspects

Somatic and germline mutations Familial or sporadic

GATOR 1 (11%) 1q21.1-q44 duplication affecting AKT3

DEPDC5: 8% of focal epilepsy

+/- focal cortical dysplasia I, IIA, IIB

Seizures from variable foci

NPRL2 and NPRL3: 1–3% of focal epilepsy ;

DEPDC5 and GATOR1 Mutations in Focal Epilepsy

» GATOR1: 21%

mTOR Inhibitors in Post-traumatic Epilepsy

Changes in brain involve mTORC1 activation Axon sprouting, increased synthesis and

phosphorylation of proteins, cell migration, and neurogenesis

TBI mouse model studies with rapamycin: GABAergic inhibition reduce mossy fiber sprouting and excitation of

dentate granule cells Decreased seizure frequency

Pharmacogenomics in Epilepsy

• How genetic factors affect response to treatment –efficacy and adverse drug reactions

• Genetic categories of variation:• Drug pharmacokinetics, drug pharmacodynamics, epilepsy

genes, ? Other

• Impact of NGS on pharmacogenomics in epilepsy and precision medicine yet to come• Collaborative projects: EpiPGX, CPNDS (The Canadian

Pharmacogenomics Network for Drug Safety)

Influence of genetic factors on response and adverse reactions to AEDs: established evidence

Mediator Genetic Factor Effect Recommendations

Pharmacokinetics & Pharmacodynamics

Variation in CYP2C9 (*2/*3)

Risk of developing concentration-dependent neurotoxicity from phenytoin

Pre-treatment genetic testing not routineMonitor clinically and drug levels

Epilepsy Genes Mutations in SLC2A1

Bi-allelic mutations in ALDH7A1

GLUT-1 deficiency

B6-dependent epilepsy

CSF/genetic testingketogenic diet

AASA/genetic testingPyridoxine or pyridoxal 5’ phosphate

Other HLA-B*15:02

HLA-B*13:01

SJS and TEN induced carbamazepine/ other aromatic AEDS in patients from Han Chinese, other South Asia groups

Increased risk carbazmazepine-induced hypersensitivity reactions-European, Japanese, all ancestries

Pre-treatment testing groups at risk (Level A)a

If positive-use alternative as 1st line

As above except all ancestries (Level B)a

S Balestrini & S Sisodiya Neuroscience Letters 2017. aAmstutz U et al Epilepsia 2014.

rash

Subject 033• 9 month presentation focal status-left arm

• Development normal

• Family history febrile seizures in father, paternal aunt and paternal great uncle

• Failed 5 anti-seizure medications

• MRI, neurometabolic, microarray negative

033 – Genetic Findings 4 weeks

Compound heterozygous mutations in POLG (each inherited by a parent) likely pathogenic ALPERS syndrome

POLG chr15:89866657 C/G rs113994097 C/TDDD NM_001126131 exon13 c.G2243C p.W748S

POLG chr15:89871929 C/G novel C/DDDD NM_001126131 exon5 c.G1157C p.R386P

033 – Genetic findings ~ 4 weeks

• The proband is a compound heterozygous for two POLGmutations – likely pathogenic– ALPERS syndrome

-> immediate impact on clinical care!?

POLG chr15:89866657 C/G rs113994097 C/TDDD NM_001126131 exon13 c.G2243C p.W748S

POLG chr15:89871929 C/G novel C/DDDD NM_001126131 exon5 c.G1157C p.R386P

Immediate clinical impact (valproic acid)

Potential Treatments

Clemizole: Dravet histamine antagonist

Bryostatin: KCNT1 Macrolide lactone: inhibit K current

Silencing microRNAs: sz & neuroprotective results regulate post-transcriptional expression of

protein coding mRNA, dendritic spine morphology

SAGE 217: Dravet, Rett syndrome

The Future

• Early diagnostic NGS in early onset epilepsy or epilepsy of unknown cause

• Drugs targeted towards genetic defect or molecular pathway or to bypass the pathway disturbed be genetic variant

• Functional test systems measuring single gene targets and multicomponent networks will be required

• Pharmacogenomics essential to reduce side effects in both patients and embryos at risk

• Potential for further novel or repurposed therapies akin to "Personalized Oncogenomic Program”

• Malformations of brain development and prevention of post traumatic epilepsy: ? Use mTOR inhibitors in the future

Rosenow et al. Epil Behav 2017;Bauer et al. Epil Behav 2017; Lindhout Lancet Neurol 2015;